JP2007007524A - Method and apparatus for producing monodisperse ultrafine particles by supercritical solution rapid cooling method - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method and an apparatus for preparing a suspension comprising mono-dispersed ultrafine particles of from nanometer order to micron order without using an organic solvent, which are capable of completely recovering the ultrafine particles by instantaneously preventing their agglomeration and crystal growth as soon as they are formed. <P>SOLUTION: In the method, a supercritical solution is rapidly cooled by injecting a coolant with a surfactant dissolved therein into the supercritical solution and by externally cooling it to form ultrafine particles. Thereby, the surfactant dissolved in the coolant is adsorbed on the surface of the precipitated particles and instantaneously suppresses the agglomeration and crystal growth of the resulting particles enabling them to remain as ultrafine particles which can be recovered as an ultrafine particle suspension of the resulting ultrafine particles uniformly mono-dispersed in an aqueous solution. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a method for producing monodispersed ultrafine particles using a supercritical fluid and a surfactant and an apparatus therefor. In particular, the present invention relates to a method and an apparatus for producing a hardly water-soluble ultrafine particle suspension of nanometer to micrometer by rapidly cooling a solute dissolved in supercritical carbon dioxide.

  When a substance is made fine particles, the surface area becomes large, and characteristics such as function, mobility, and permeability change. Conventionally, fine particles are obtained by grinding or an impact type pulverizer, but it is difficult to produce monodisperse fine particles because there is a limit to pulverization and the pulverized fine particles easily aggregate.

In recent years, a method for producing fine particles using a supercritical fluid has attracted attention. That is, after dissolving a solute in a supercritical fluid, when supercritical carbon dioxide is injected into the atmosphere from a nozzle, the carbon dioxide rapidly vaporizes and volatilizes, and the solute precipitates due to a pressure drop to generate fine particles. Is the supercritical fluid rapid expansion method (RESS). In this method, the generated particles are likely to aggregate, and the more the generated particles become finer, the more difficult it is to recover. Therefore, as a modified method of RESS, supercritical solution is injected into the recovered solution to recover and prevent aggregation of poorly water-soluble particles. Thus, the RESAS method for producing fine particles has been developed.

The rapid expansion method (RESS) studied by Matson et al. Has the advantage of not using an organic solvent, and is effective for atomization of solutes soluble in supercritical carbon dioxide, and has been published in many patents and literature (non-patent literature) See 1-3). The RESAS method improved by Young et al. Also adopts the basic concept of RESS. Both RESS and RESAS are characterized by high supersaturation of the solute dissolved in the supercritical fluid under rapid decompression.
A surfactant is often used to disperse the fine particles in the solution. Such a method is also applied to the RESAS method and the SAS method (see Patent Document 1-2).
A method for producing ultrafine particles by dissolving a solute with an organic solvent and then rapidly cooling it through a nozzle was patented by Williams et al. (See Patent Document 3).

The RESS method easily generates particles of micron or larger, but it is difficult to produce nano-sized particles of submicron, particularly 100 nanometers or less (see Non-Patent Document 3). And the collection | recovery of the microparticles injected in air | atmosphere also becomes a big difficulty. The RESAS method has the advantage that the recovery problem can be almost solved for the slightly water-soluble fine particles, and if a fine nozzle is used, submicron fine particles can be produced. However, in order to produce nano-sized ultrafine particles, a submicron or nano-sized ultrafine nozzle is required, and there is a drawback that it is difficult to manufacture the nozzle and the flow rate is limited, which makes it difficult to apply to industry. Moreover, in the quick injection freezing method like patent document 3, since organic solvent is used, problems, such as the purity of a chemical | medical agent and an environmental contamination, are pointed out when producing microparticles | fine-particles, such as a chemical | medical agent.
Pace et al., US 6177103 Henriksen et al., US 6576264 Williams et al., US 6862890 B2 Matson et al., "Rapid Expansion of Supercritical Fluid Solutions: Solute Formation of Powders, Thin Films, and Fibers," Ind. Eng. Chem. Res. 26 (1987) 2298-2306. Young, et al., Biotechnology. Prog., “Rapid Expansion from Supercritical to aqueous solution to produce suspensions of water-insoluble drugs 16 (2000) 402-407. Jung et al., "Particle design using supercritical fluids: Literature and patent survey," Journal of Supercritical Fluids 20 (2001) 179-219.

  A method for atomizing a drug using an organic solvent has been studied, but the supercritical fluid method is advantageous in terms of reducing environmental burden and improving safety. The solubility of a solute dissolved in a supercritical fluid depends on pressure and temperature. The degree of supersaturation is sensitive to changes in pressure, and the solute supersaturation changes drastically with decreasing pressure when rapidly expanding. Supercritical fluids have a pressure loss when passing through valves and pipes, so the solute nucleates before the fluid reaches the nozzle and grows to the micron or micron level due to aggregation and merger. In order to adjust smaller ultrafine particles, it is necessary to develop a means for adjusting the degree of supersaturation of solutes and a method for quickly stopping crystal growth.

In the RESS method and RESAS method, the size of the generated particles greatly depends on the size of the fine nozzle. The smaller the nozzle diameter, the finer the generated particles. Most pressure-resistant nozzles are made of metal, and the diameter of nozzles that can be processed by laser is about several tens of microns. Moreover, even if there is a special fine nozzle, the flow rate from the fine nozzle is small, and mass production of fine particles is difficult.
The present invention provides a method for producing monodispersed ultrafine particles without using an organic solvent and a fine nozzle for making fine particles.

In order to solve the above problems, the present invention does not use an organic solvent and a fine nozzle for atomization, immediately after nucleation of a solute in a supercritical solution, adsorbs a surfactant on the surface of the ultrafine particle, and immediately It is intended to stop the crystal growth of ultrafine particles and produce monodisperse ultrafine particles.
That is, the gist of the present invention is the following (1) to (10) control method for producing monodisperse ultrafine particles.
(1) By rapidly cooling the supercritical solution, the temperature of the supercritical solution is greatly lowered from the critical point to below the critical point, and the liquid phase or liquid-solid state is rapidly changed from the supercritical state to the non-supercritical state. Control method to make both phases.
(2) A solution in which a solute does not dissolve is cooled to a temperature lower than the critical point of the supercritical fluid, and this cooling liquid is passed through a nozzle and sprayed onto the supercritical solution to form a mist droplet or a fine fluid. A cooling method that utilizes the intense cooling effect when the cooling phase is ejected. A method of cooling the entire ultrafine particle production high-pressure chamber from the outside when spraying the coolant.
(3) A method for producing ultrafine particles by achieving high supersaturation with a significant decrease in the solubility of the solute dissolved in the supercritical solution by the above methods (1) and (2) and by precipitation of the solute.
(4) A method for producing the solute ultrafine particles, wherein the solute is precipitated in the coolant by bringing the supercritical solution into contact with the coolant.
(5) A method for producing the ultrafine particles, wherein the formed ultrafine particles are captured and recovered in a coolant.
(6) A method in which aggregation of primary ultrafine particles and crystal growth are stopped by adsorbing the surfactant added in the cooling liquid to the surface of the ultrafine particles.
(7) A method for controlling the dispersion effect of fine particles by changing the kind, addition concentration, and mixing ratio of single or plural hydrophilic surfactants.
(8) A method of controlling the cooling effect by changing the injection amount of the cooling liquid, the injection temperature and pressure, and the temperature and pressure of the ultrafine particle production high pressure chamber.
(9) A method in which the ultrafine particles are completely recovered as a monodispersed suspension in a sealed container.
(10) A method for rapidly producing a water-insoluble ultrafine particle suspension, wherein the formation, dispersion and recovery of ultrafine particles are simultaneously completed by the methods (1) to (9) above.

  The apparatus according to the present invention includes a supercritical fluid control unit capable of adjusting the pressure and temperature for dissolving a solute, a coolant control unit capable of adjusting an appropriate coolant temperature and pressure, an injection unit, and an ultrafine particle recovery unit. .

  The present invention does not use an organic solvent, for example, using non-toxic supercritical carbon dioxide as a solvent, forms water-insoluble ultrafine particles from nanometer to micrometer, prevents aggregation of primary particles, A fully recovered, monodispersed ultrafine particle suspension can be rapidly produced.

Embodiments for carrying out the present invention will be described with reference to FIGS. 1 and 2. FIG. 1 is a view for explaining an apparatus according to an embodiment of the present invention. FIG. 2 is a schematic diagram for explaining the action of the cooling liquid and the surfactant, the generation mechanism of the ultrafine particles, and the formation process of the monodispersed ultrafine particle suspension. An explanation will be given by taking as an example fine particles of a poorly water-soluble substance dissolved in supercritical carbon dioxide with cooling water containing a hydrophilic surfactant.
First, each item in the present invention will be described.
Ultrafine particles: Originally, only particles around nanometers are considered to be nanoparticles, but in the field of drug fine particle production, particles of 1 micrometer or less are called nanoparticles. In the present invention, particles from nano-order to micro-order are called ultrafine particles.
Supercritical solution: A supercritical fluid containing a solute. Originally, a supercritical fluid is a fluid at a temperature and pressure exceeding the critical point of a substance, and has a much higher ability to dissolve a substance than a gas or liquid. Examples of the supercritical fluid in the embodiment include supercritical carbon dioxide that is not toxic and easy to operate. Other supercritical fluids that are easy to handle include ethane, propane, methanol, ethanol, ammonia, and xenon.
Surfactant: A phenomenon in which a substance is adsorbed on the interface and its interfacial tension decreases is called surface activity, and an effective substance that exhibits remarkable surface activity in a small amount is called a surfactant. In consideration of safety, the surfactant in the examples was selected to be a hydrophilic non-ionized surfactant of about HLB15 toward the slightly water-soluble drug fine particles. In addition to nonionic surfactants, anionic surfactants, cationic surfactants, amphoteric surfactants and the like can be considered.
Solutes soluble in supercritical fluids: Nearly one-third of all drugs are difficult to dissolve in water, but drugs that are soluble in supercritical carbon dioxide are not uncommon. Examples include aspirin as an anti-inflammatory agent and lidocaine used for anesthesia and cardiac arrhythmia. In addition, pigments, cosmetics, polymer materials, etc. are also conceivable.
Suspension: A solution in which solid particles are dispersed in a liquid. Or it is also called a colloidal solution or a suspension. The suspension obtained in the examples constitutes water, ultrafine particles and a surfactant.

In the present invention, an appropriate amount of solute is put into the high-pressure chamber 10 and adjusted to a temperature and pressure exceeding the critical point of supercritical carbon dioxide (critical temperature 31.2 ° C., critical pressure 7.38 MPa), and the solute is supercritical carbon dioxide. Dissolve in. If necessary, stir with a stirrer to dissolve the solute.
Next, after adjusting the selected cooling liquid to a temperature lower than the critical temperature, it is put into the cylinder pump 11 and a pressure higher by several MPa than the pressure of the high pressure chamber 10 is applied, and the cooling liquid is discharged from the nozzle 8 installed in the high pressure chamber 10. The supercritical carbon dioxide solution in the vicinity of the surface of the droplet 15 is rapidly cooled by spraying at high speed in the form of a mist.
Due to the rapid cooling, the solute 17 in the high-pressure chamber 10 starts to be deposited on the surface of the droplet. Due to the stirring effect and the diffusion movement, the precipitated solid solute enters the liquid and comes into contact with the surfactant molecules 16. The surfactant 16 is adsorbed on the surface of the solid particles, prevents aggregation of the particles and stops crystal growth. Therefore, the monodispersed ultrafine particles 19 having surface hydrophilicity can be produced in the state of the suspension 20.

  Next, examples will be described. Lidocaine and aspirin, which have high solubility in supercritical carbon dioxide, were used as model drugs. Tween-80 and sucrose fatty acid ester, which are used as food additives and have no safety effects on the human body or environment, have extremely high safety, and are used as surfactants.

After a predetermined amount (0.025%) of aspirin is put into the high-pressure chamber 10, carbon dioxide is introduced, adjusted to 50 ° C. and 15 MPa, and aspirin is dissolved in supercritical carbon dioxide. On the other hand, a jelly-like nonionic surfactant Tween-80 (HLB = 15) is completely dissolved in water at about 70 ° C. and then cooled to about 10 ° C. This Tween-80 aqueous solution (0.5 wt%) is put into the cooling container 11. This cooling liquid is injected into the high-pressure chamber 10 through a nozzle 8 having a diameter of about 0.2 mm under the condition of a pressure of 20 MPa. After stirring for several minutes, the valve of the high-pressure chamber was opened and the pressure was slowly reduced to atmospheric pressure to recover the ultrafine particle suspension. The particle size in the suspension was measured by laser scattering analysis. The results are shown in Table 1 and FIG. It was found that ultrafine particles having an average of about 280 nanometers were formed.

Table 1: Size distribution measurement results of ultrafine aspirin particles

A predetermined amount (about 0.05 wt%) of lidocaine is put into the high-pressure chamber 10, carbon dioxide is introduced, the temperature is adjusted to 50 ° C. and 10 MPa, and lidocaine is dissolved in supercritical carbon dioxide. On the other hand, a powdered nonionic surfactant sucrose fatty acid ester (S-1570, HLB = 15) is completely dissolved in water at about 70 ° C. and then cooled to about 5 ° C. This S-1570 cooling liquid (0.03 wt%) is put into the cooling container 11 and this cooling liquid is injected into the ultrafine particle production chamber 9 through the nozzle 8 having a diameter of about 0.2 mm under the condition of a pressure of 15 MPa. The entire high-pressure chamber 10 is placed in the cooling bath 13 and filled with ice water to enhance the cooling effect. The inside of the high-pressure chamber 10 is stirred for several minutes to uniformly disperse the generated particles and the liquid therein. After releasing the pressure, the liquid in which the generated particles were suspended was collected, and the particle size was measured by laser scattering analysis. The results are shown in Table 2 and FIG. It was found that ultrafine particles with an average of 62 nanometers were formed from 10 nanometers to 120 nanometers.

Table 2: Size distribution measurement results of lidocaine ultrafine particles

  INDUSTRIAL APPLICABILITY The present invention can be used in a wide range of fields such as pharmaceuticals, materials, and the chemical industry for producing ultrafine particles and producing monodispersed ultrafine particle suspensions.

It is a figure which shows the apparatus of this invention. It is an image figure which shows the formation mechanism of a monodispersed ultrafine particle. FIG. 3 is a size distribution diagram of aspirin ultrafine particles prepared in Example 1 of the present invention. It is a size distribution figure of the lidocaine ultrafine particle made in this invention Example 2.

Explanation of symbols

DESCRIPTION OF SYMBOLS 1 Carbon dioxide cylinder 2 Valve 3 Cooling machine 4 Pump 5 Pressure regulator 6 Heater 7 Supercritical carbon dioxide reservoir 8 Injection part 9 Stirrer 10 Ultrafine particle production chamber 11 High-pressure cylinder pump for cooling liquid injection 12 Solute injector 13 External cooling tank 14 Recovery Container 15 Coolant Droplet 16 Surfactant 17 Ultrafine Particles Precipitated from Supercritical Solution 18 Cooling Liquid Merged 19 Monodisperse Particles with Surface Hydrophilicity 20 Ultrafine Particle Suspension Dispersed in Solution

Claims (5)

A solute ultrafine atomization technology characterized by mixing a supercritical fluid in which a solute is dissolved and a cooling liquid, rapidly cooling to a temperature below the critical temperature, and precipitating the solute as ultrafine particles. Coolant is injected into a high-pressure chamber containing the supercritical fluid in which the solute is dissolved, and the supercritical fluid is rapidly cooled to below the critical temperature, thereby greatly reducing the solubility of the solute and making it a poor solvent. 2. The method for producing ultrafine particles of a solute according to claim 1, wherein the particles are precipitated as fine particles. The cooling liquid is a solute-insoluble solution, which is rapidly injected into a supercritical fluid in which a solute is dissolved, a solution kept below the supercritical point, preferably a solution lower than the critical temperature by 20 ° C. or more. 2. A method for making ultrafine particles of solute 2. 4. The method for producing monodispersed ultrafine particles according to claim 1, wherein the produced ultrafine particles are recovered as monodispersed fine particles using a cooling liquid in which one or more kinds of surfactants are dissolved in a predetermined concentration. 5. The apparatus for producing monodispersed ultrafine particles according to claim 1, wherein the cooling liquid injection part is composed of a fine nozzle or a perforated plate, and a high-pressure chamber equipped with an internal stirrer and an external cooling tank is used.

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